Bristol Myers Squibb Research and Early Development, P.O. Box 4000, Princeton, NJ, 08543, USA.
Mol Imaging Biol. 2024 Apr;26(2):301-309. doi: 10.1007/s11307-023-01889-4. Epub 2023 Dec 20.
In cancer immunotherapy, the blockade of the interaction between programmed death-1 and its ligand (PD-1:PD-L1) has proven to be one of the most promising strategies. However, as mechanisms of resistance to PD-1/PD-L1 inhibition include variability in tumor cell PD-L1 expression in addition to standard tumor biopsy PD-L1 immunohistochemistry (IHC), a comprehensive and quantitative approach for measuring PD-L1 expression is required. Herein, we report the development and characterization of an F-PD-L1-binding macrocyclic peptide as a PET tracer for the comprehensive evaluation of tumor PD-L1 expression in cancer patients.
F-BMS-986229 was characterized for PD-L1 expression assessment by autoradiography or PET imaging. F-BMS-986229 was utilized to evaluate tumor PD-L1 target engagement in competition with a macrocyclic peptide inhibitor of PD-L1 (BMS-986189) over a range of doses using PET imaging. A whole-body radiation dosimetry study of F-BMS-986229 in healthy non-human primates (NHPs) was performed.
In vitro autoradiography showed an 8:1 binding ratio in L2987(PD-L1 +) vs. HT-29 (PD-L1-) tumors, more than 90% of which could be blocked with 1 nM of BMS-986189. Ex vivo autoradiography showed that F-BMS-986229 detection was penetrant over a series of sections spanning the entire L2987 tumor. In vivo PET imaging in mice demonstrated a 5:1 tracer uptake ratio (at 90-100 min after tracer administration) in L2987 vs. HT-29 tumors and demonstrated 83%-93% specific binding of BMS-986189 within those dose ranges. In a healthy NHP dosimetry study, the resultant whole-body effective dose was 0.025 mSv/MBq.
F-BMS-986229 has been preclinically characterized and exhibits high target specificity, low background uptake, and a short blood half-life supportive of same day imaging in the clinic. As the PET tracer, F-BMS-986229 shows promise in the quantification of PD-L1 expression, and its use in monitoring longitudinal changes in patients may provide insights into PD-1:PD-L1 immuno-therapy treatment outcomes.
在癌症免疫疗法中，阻断程序性死亡-1 与其配体（PD-1：PD-L1）之间的相互作用已被证明是最有前途的策略之一。然而，由于对 PD-1/PD-L1 抑制的耐药机制包括肿瘤细胞 PD-L1 表达的可变性以及标准肿瘤活检 PD-L1 免疫组化（IHC），因此需要一种全面和定量的方法来测量 PD-L1 表达。在此，我们报告了一种 F-PD-L1 结合大环肽的开发和表征，作为一种 PET 示踪剂，用于全面评估癌症患者的肿瘤 PD-L1 表达。
通过放射自显影或 PET 成像对 F-BMS-986229 进行 PD-L1 表达评估的特征描述。使用 PET 成像，在一系列剂量下，利用 PD-L1 抑制剂 BMS-986189 与 F-BMS-986229 竞争，评估 F-BMS-986229 在肿瘤 PD-L1 靶标结合中的作用。在健康非人灵长类动物（NHPs）中进行了 F-BMS-986229 的全身放射性剂量学研究。
体外放射自显影显示 L2987（PD-L1+）与 HT-29（PD-L1-）肿瘤之间的结合比为 8:1，其中超过 90%可以被 1 nM 的 BMS-986189 阻断。离体放射自显影显示 F-BMS-986229 检测在跨越整个 L2987 肿瘤的一系列切片中具有穿透力。在小鼠体内 PET 成像中，L2987 与 HT-29 肿瘤的示踪剂摄取比为 5:1（在示踪剂给药后 90-100 分钟），并在这些剂量范围内显示 BMS-986189 的 83%-93%特异性结合。在健康 NHP 剂量学研究中，全身有效剂量为 0.025 mSv/MBq。
F-BMS-986229 已在临床前进行了特征描述，表现出高靶特异性、低背景摄取和较短的血液半衰期，支持当天在临床进行成像。作为 PET 示踪剂，F-BMS-986229 有望用于定量 PD-L1 表达，其在监测患者纵向变化中的应用可能为 PD-1：PD-L1 免疫治疗结果提供见解。
